Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 266

et al., 1998 ). For instance, CHOP is suggested to upregulate proapoptotic
BCL2 family members, like BAK/BAD, while downregulating antiapop-
totic BCL2 and increasing reactive oxygen species (ROS), which together
favor cytochrome c release from mitochondria and trigger apoptosis ( Ma
and Hendershot, 2004 ). ER stress conditions also promote calcium release
from the ER to the cytosol, thereby favoring activation of calpains, which
then cleave and activate caspase-12 ( Nakagawa and Yuan, 2000 ). Then, cas-
pase-12 in turn cleaves and activates cytosolic caspase-9, triggering apop-
tosis in a manner independent of cytochrome c release from mitochondria.
In summary, UPR is crucial to malignant cell survival in the cytotoxic
environment within a tumor. These conditions activate UPR as an adaptive
response that allows tumor cells to persist. For this reason, the possibility of
developing chemical agents that target some key UPR components is an
interesting therapeutic option. On the another hand, if ER stress conditions
prevail and cellular homeostasis cannot be reinstated, UPR can trigger apop-
tosis. Indeed, as we have detailed here, UPR can sensitize tumor cells to cer-
tain anticancer agents. However, given that in tumor cells protein expression
and signaling are frequently altered in ways that allow these cells to avoid
apoptosis, we suspect that the balance is tilted toward UPR as a prosurvival
response. In any case, an integrated vision of the UPR in tumor cells is
essential to understand how this response contributes to the cancer growth.
7. CONCLUSION AND PERSPECTIVES
The ER is a fascinating organelle that plays a central role within
the cell. This extremely complex and heterogeneous cellular compartment
spreads throughout the cytoplasm forming various subdomains with diverse
morphology and function. As such, the ER is a highly dynamic structure
that modulates organization according to cellular needs and participates in
protein synthesis, lipid metabolism, calcium handling, metabolic regulation
and signaling. All of the latter processes are essential to the cell, making the
ER susceptible to a variety of perturbations. The degree of complexity
associated with optimal ER function positions this organelle as the largest
stress sensor of the cell and, therefore, a major contributing factor to disease.
Under stress conditions, the ER induces the UPR, a well-known
signaling cascade that acts as an important regulator of cellular homeo-
stasis. The UPR generates an integrated genetic response that serves to
re-establish homeostasis in the always-varying intracellular or extracellular
milieu. Failure to regain homeostasis causes the UPR to activate cell death